Thioxanthine derivatives as myeloperoxidase inhibitors

ABSTRACT

There is disclosed the use of a compound of formula (Ia) or (Ib) 
                         
wherein R 1 , R 2 , R 3 , R 4 , X and Y are as defined in the specification, and pharmaceutically acceptable salts thereof, in the manufacture of a medicament, for the treatment or prophylaxis of diseases or conditions in which inhibition of the enzyme myeloperoxidase (MPO) is beneficial. Certain novel compounds of formula (Ia) or (Ib) and pharmaceutically acceptable salts thereof are disclosed, together with processes for their preparation. The compounds of formulae (Ia) and (Ib) are MPO inhibitors and are thereby particularly useful in the treatment or prophylaxis of neuroinflammatory disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/511,537, which was the National Stage of International ApplicationNo. PCT/SE03/00617, filed Apr. 15, 2003, which claims the benefit under35 U.S.C. §119 (a)-(d) of Swedish application nos. 0201193-0, filed Apr.19, 2002, and 0202239-0, filed Jul. 17, 2002, which are all herebyincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to the use of thioxanthine derivatives asinhibitors of the enzyme myeloperoxidase (MPO). Certain novelthioxanthine derivatives are also disclosed together with processes fortheir preparation, compositions containing them and their use intherapy.

BACKGROUND OF THE INVENTION

Myeloperoxidase (MPO) is a heme-containing enzyme found predominantly inpolymorphonuclear leukocytes (PMNs). MPO is one member of a diverseprotein family of mammalian peroxidases that also includes eosinophilperoxidase, thyroid peroxidase, salivary peroxidase, lactoperoxidase,prostaglandin H synthase, and others. The mature enzyme is a dimer ofidentical halves. Each half molecule contains a covalently bound hemethat exhibits unusual spectral properties responsible for thecharacteristic green colour of MPO. Cleavage of the disulphide bridgelinking the two halves of MPO yields the hemi-enzyme that exhibitsspectral and catalytic properties indistinguishable from those of theintact enzyme. The enzyme uses hydrogen peroxide to oxidize chloride tohypochlorous acid. Other halides and pseudohalides (like thiocyanate)are also physiological substrates to MPO.

PMNs are of particular importance for combating infections. These cellscontain MPO, with well documented microbicidal action. PMNs actnon-specifically by phagocytosis to engulf microorganisms, incorporatethem into vacuoles, termed phagosomes, which fuse with granulescontaining myeloperoxidase to form phagolysosomes. In phagolysosomes theenzymatic activity of the myeloperoxidase leads to the formation ofhypochlorous acid, a potent bactericidal compound. Hypochlorous acid isoxidizing in itself, and reacts most avidly with thiols and thioethers,but also converts amines into chloramines, and chlorinates aromaticamino acids. Macrophages are large phagocytic cells which, like PMNs,are capable of phagocytosing microorganisms. Macrophages can generatehydrogen peroxide and upon activation also produce myeloperoxidase. MPOand hydrogen peroxide can also be released to the outside of the cellswhere the reaction with chloride can induce damage to adjacent tissue.

Linkage of myeloperoxidase activity to disease has been implicated inneurological diseases with a neuroinflammatory response includingmultiple sclerosis, Alzheimer's disease, Parkinson's disease and strokeas well as other inflammatory diseases or conditions like asthma,chronic obstructive pulmonary disease, cystic fibrosis, atherosclerosis,inflammatory bowel disease, renal glomerular damage and rheumatoidarthritis. Lung cancer has also been suggested to be associated withhigh MPO levels.

WO 01/85146 discloses various compounds that are MPO inhibitors and arethereby useful in the treatment of chronic obstructive pulmonary disease(COPD). 3-n-Propyl-2-thioxanthine is disclosed in Drug DevelopmentResearch, 1999, 47, 45-53. 3-Isobutyl-6-thioxanthine is disclosed in J.Chem. Soc., 1962, 1863. 2-Thioxanthine is commercially available.

The present invention relates to a group of thioxanthine derivativesthat surprisingly display useful properties as inhibitors of the enzymeMPO.

DISCLOSURE OF THE INVENTION

According to the present invention, there is provided the use of acompound of formula (Ia) or (Ib)

wherein:one of X and Y represents S, and the other represents O or S;R¹ represents hydrogen or C1 to 6 alkyl;R² represents hydrogen or C1 to 6 alkyl; said alkyl group beingoptionally substituted by:i) a saturated or partially unsaturated 3- to 7-membered ring optionallyincorporating one or two heteroatoms selected independently from O, Nand S, and optionally incorporating a carbonyl group; said ring beingoptionally substituted by one or more substituents selected fromhalogen, hydroxy, C1 to 6 alkoxy and C1 to 6 alkyl; said alkyl beingoptionally further substituted by hydroxy or C1 to 6 alkoxy; orii) C1 to 6 alkoxy; oriii) an aromatic ring selected from phenyl, furyl or thienyl; saidaromatic ring being optionally further substituted by halogen, C1 to 6alkyl or C1 to 6 alkoxy;R³ and R⁴ independently represent hydrogen or C1 to 6 alkyl;or a pharmaceutically acceptable salt thereof, in the manufacture of amedicament, for the treatment or prophylaxis of diseases or conditionsin which inhibition of the enzyme MPO is beneficial.

The compounds of formula (Ia) or (Ib) may exist in enantiomeric forms.Therefore, all enantiomers, diastereomers, racemates and mixturesthereof are included within the scope of the invention.

It will be appreciated that when R³ in formulae (Ia) and (Ib) representshydrogen, the two alternative representations (Ia) and (Ib) aretautomeric forms of the same compound. All such tautomers and mixturesof tautomers are included within the scope of the present invention.

A more particular aspect of the invention provides the use of a compoundof formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof,in the manufacture of a medicament, for the treatment or prophylaxis ofneuroinflammatory disorders.

According to the invention, there is also provided a method of treating,or reducing the risk of, diseases or conditions in which inhibition ofthe enzyme MPO is beneficial which comprises administering to a personsuffering from or at risk of, said disease or condition, atherapeutically effective amount of a compound of formula (Ia) or (Ib),or a pharmaceutically acceptable salt thereof.

More particularly, there is also provided a method of treating, orreducing the risk of, neuroinflammatory disorders in a person sufferingfrom or at risk of, said disease or condition, wherein the methodcomprises administering to the person a therapeutically effective amountof a compound of formula (Ia) or (Ib), or a pharmaceutically acceptablesalt thereof.

In another aspect the invention provides a pharmaceutical formulationcomprising a therapeutically effective amount of a compound of formula(Ia) or (Ib), or a pharmaceutically acceptable salt thereof, inadmixture with a pharmaceutically acceptable adjuvant, diluent orcarrier, for use in the treatment or prophylaxis of diseases orconditions in which inhibition of the enzyme MPO is beneficial.

In another more particular aspect the invention provides apharmaceutical formulation comprising a therapeutically effective amountof a compound of formula (Ia) or (Ib), or a pharmaceutically acceptablesalt thereof, in admixture with a pharmaceutically acceptable adjuvant,diluent or carrier, for use in the treatment or prophylaxis ofneuroinflammatory disorders.

In one embodiment, there is provided the use of a compound of formula(Ia) or (Ib) wherein at least one of X and Y represents S, and the otherrepresents O or S; R¹ represents hydrogen or C1 to 6 alkyl; R²represents hydrogen or C1 to 6 alkyl; said alkyl group being optionallysubstituted by C3 to 7 cycloalkyl, C1 to 4 alkoxy, or an aromatic ringselected from phenyl, furyl or thienyl; said aromatic ring beingoptionally further substituted by halogen, C1 to 4 alkyl or C1 to 4alkoxy; R³ and R⁴ independently represent hydrogen or C1 to 6 alkyl; ora pharmaceutically acceptable salt, enantiomer or racemate thereof, inthe manufacture of a medicament, for the treatment or prophylaxis ofdiseases or conditions in which inhibition of the enzyme MPO isbeneficial.

In another embodiment, there is provided the use of a compound offormula (Ia) or (Ib) wherein at least one of X and Y represents S, andthe other represents O or S; R¹ represents hydrogen or C1 to 6 alkyl; R²represents hydrogen or C1 to 6 alkyl; said alkyl group being optionallysubstituted by: i) a saturated or partially unsaturated 3- to 7-memberedring optionally incorporating one or two heteroatoms selectedindependently from O, N and S, and optionally incorporating a carbonylgroup; said ring being optionally substituted by one or moresubstituents selected from halogen, hydroxy, C1 to 6 alkoxy and C1 to 6alkyl; said alkyl being optionally further substituted by hydroxy or C1to 4 alkoxy; or ii) C1 to 4 alkoxy; or iii) an aromatic ring selectedfrom phenyl, furyl or thienyl; said aromatic ring being optionallyfurther substituted by halogen, C1 to 4 alkyl or C1 to 4 alkoxy; R³ andR⁴ independently represent hydrogen or C1 to 6 alkyl; or apharmaceutically acceptable salt thereof, in the manufacture of amedicament, for the treatment or prophylaxis of diseases or conditionsin which inhibition of the enzyme MPO is beneficial.

In one embodiment, the invention relates to the use of compounds offormula (Ia) or (Ib) wherein X represents S and Y represents O.

In another embodiment, R³ in formula (Ia) or (Ib) represents hydrogen.

In another embodiment, R² in formula (Ia) or (Ib) represents optionallysubstituted C1 to 6 alkyl.

In another embodiment, R² in formula (Ia) or (Ib) represents C1 to 6alkyl substituted by a saturated or partially unsaturated 3- to7-membered ring optionally incorporating one or two heteroatoms selectedindependently from O, N and S, and optionally incorporating a carbonylgroup; said ring being optionally substituted by one or moresubstituents selected from halogen, hydroxy, C1 to 6 alkoxy and C1 to 6alkyl; said alkyl being optionally further substituted by hydroxy or C1to 6 alkoxy.

In another embodiment, R² in formula (Ia) or (Ib) represents methylene,ethylene or trimethylene substituted by cyclopropyl, cyclohexyl,tetrahydrofuranyl or morpholinyl.

In another embodiment, R² in formula (Ia) or (Ib) represents C1 to 6alkyl substituted by C1 to 6 alkoxy.

In another embodiment, R² in formula (Ia) or (Ib) represents ethylene ortrimethylene substituted by methoxy or ethoxy.

When X represents S and Y represents O, a further embodiment comprisescompounds of formula (Ia) or (Ib) wherein R¹ represents hydrogen.

When X represents S and Y represents O, a yet further embodimentcomprises compounds of formula (Ia) or (Ib) wherein R⁴ representshydrogen.

When X represents O and Y represents S, a further embodiment comprisescompounds of formula (Ia) or (Ib) wherein R¹ represents C1 to 6 alkyl.

When X represents O and Y represents S, a yet further embodimentcomprises compounds of formula (Ia) or (Ib) wherein R⁴ represents C1 to6 alkyl.

In one embodiment, the invention relates to the use of compounds offormula (Ia) or (Ib) wherein X represents S and Y represents O; R²represents optionally substituted C1 to 6 alkyl; and R¹, R³ and R⁴ eachrepresent hydrogen.

In one embodiment, the invention relates to the use of compounds offormula (Ia) or (Ib) wherein X represents S and Y represents O; R²represents C1 to 6 alkyl substituted by a saturated or partiallyunsaturated 3- to 7-membered ring optionally incorporating one or twoheteroatoms selected independently from O, N and S, and optionallyincorporating a carbonyl group; said ring being optionally substitutedby one or more substituents selected from halogen, hydroxy, C1 to 6alkoxy and C1 to 6 alkyl; said alkyl being optionally furthersubstituted by hydroxy or C1 to 6 alkoxy; and R¹, R³ and R⁴ eachrepresent hydrogen.

In one embodiment, the invention relates to the use of compounds offormula (Ia) or (Ib) wherein X represents S and Y represents O; R²represents C1 to 6 alkyl substituted by C1 to 6 alkoxy; and R¹, R³ andR⁴ each represent hydrogen.

A specific aspect of the invention concerns the use of the followingcompounds of formula (Ia) or (Ib):

-   1,3-diisobutyl-8-methyl-6-thioxanthine;-   1,3-dibutyl-8-methyl-6-thioxanthine;-   3-isobutyl-1,8-dimethyl-6-thioxanthine;-   3-(2-methylbutyl)-6-thioxanthine;-   3-isobutyl-8-methyl-6-thioxanthine;-   3-isobutyl-2-thioxanthine;-   3-isobutyl-2,6-dithioxanthine;-   3-isobutyl-8-methyl-2-thioxanthine;-   3-isobutyl-7-methyl-2-thioxanthine;-   3-cyclohexylmethyl-2-thioxanthine;-   3-(3-methoxypropyl)-2-thioxanthine;-   3-cyclopropylmethyl-2-thioxanthine;-   3-isobutyl-1-methyl-2-thioxanthine;-   3-(2-tetrahydrofuryl-methyl)-2-thioxanthine;-   3-(2-methoxy-ethyl)-2-thioxanthine;-   3-(3-(1-morpholinyl)-propyl)-2-thioxanthine;-   3-(2-furyl-methyl)-2-thioxanthine;-   3-(4-methoxybenzyl)-2-thioxanthine;-   3-(4-fluorobenzyl)-2-thioxanthine;-   3-phenethyl-2-thioxanthine;-   (+)-3-(2-tetrahydrofuryl-methyl)-2-thioxanthine;-   (−)-3-(2-tetrahydrofuryl-methyl)-2-thioxanthine;-   3-n-butyl-2-thioxanthine;-   3-n-propyl-2-thioxanthine;-   3-isobutyl-6-thioxanthine;-   2-thioxanthine;    and pharmaceutically acceptable salts thereof.

Unless otherwise indicated, the term “C1 to 6 alkyl” referred to hereindenotes a straight or branched chain alkyl group having from 1 to 6carbon atoms. Examples of such groups include methyl, ethyl, 1-propyl,n-butyl, iso-butyl, tert-butyl, pentyl and hexyl.

The term “C1 to 4 alkyl” is to be interpreted analogously.

Unless otherwise indicated, the term “C3 to 7 cycloalkyl” referred toherein denotes a cyclic alkyl group having from 3 to 7 carbon atoms.Examples of such groups include cyclopropyl, cyclopentyl and cyclohexyl.

Unless otherwise indicated, the term “C1 to 6 alkoxy” referred to hereindenotes a straight or branched chain alkoxy group having from 1 to 6carbon atoms. Examples of such groups include methoxy, ethoxy,1-propoxy, 2-propoxy and tert-butoxy.

The term “C1 to 4 alkoxy” is to be interpreted analogously.

Unless otherwise indicated, the term “halogen” referred to hereindenotes fluoro, chloro, bromo and iodo.

Examples of a saturated or partially unsaturated 3- to 7-membered ringoptionally incorporating one or two heteroatoms selected independentlyfrom O, N and S, and optionally incorporating a carbonyl group includecyclopropyl, cyclopentyl, cyclohexyl, cyclopentanone, tetrahydrofuran,pyrrolidine, piperidine, morpholine, piperazine, pyrrolidinone andpiperidinone. Particular examples include cyclopropyl, cyclohexyl,tetrahydrofuranyl (tetrahydrofuryl) and morpholinyl.

Certain compounds of formula (Ia) or (Ib) are novel. Therefore a furtheraspect of the invention provides the following novel compounds offormula (Ia) or (Ib)

wherein:X represents S, and Y represents O;R¹ represents hydrogen or C1 to 6 alkyl;R² represents C1 to 6 alkyl substituted by a saturated or partiallyunsaturated 3- to 7-membered ring optionally incorporating one or twoheteroatoms selected independently from O, N and S, and optionallyincorporating a carbonyl group; said ring being optionally substitutedby one or more substituents selected from halogen, hydroxy, C1 to 6alkoxy and C1 to 6 alkyl; said alkyl being optionally furthersubstituted by hydroxy or C1 to 6 alkoxy;R³ and R⁴ independently represent hydrogen or C1 to 6 alkyl;and pharmaceutically acceptable salts thereof.

A further aspect of the invention provides the following novel compoundsof formula (Ia) or (Ib):

-   1,3-diisobutyl-8-methyl-6-thioxanthine;-   1,3-dibutyl-8-methyl-6-thioxanthine;-   3-isobutyl-1,8-dimethyl-6-thioxanthine;-   3-(2-methylbutyl)-6-thioxanthine;-   3-isobutyl-8-methyl-6-thioxanthine;-   3-isobutyl-2-thioxanthine;-   3-isobutyl-2,6-dithioxanthine;-   3-isobutyl-8-methyl-2-thioxanthine;-   3-isobutyl-7-methyl-2-thioxanthine;-   3-cyclohexylmethyl-2-thioxanthine;-   3-(3-methoxypropyl)-2-thioxanthine;-   3-cyclopropylmethyl-2-thioxanthine;-   3-isobutyl-1-methyl-2-thioxanthine;-   3-(2-tetrahydrofuryl-methyl)-2-thioxanthine;-   3-(2-methoxy-ethyl)-2-thioxanthine;-   3-(3-(1-morpholinyl)-propyl)-2-thioxanthine;-   3-(2-furyl-methyl)-2-thioxanthine;-   3-(4-methoxybenzyl)-2-thioxanthine;-   3-(4-fluorobenzyl)-2-thioxanthine;-   3-phenethyl-2-thioxanthine;-   (+)-3-(2-tetrahydrofuryl-methyl)-2-thioxanthine;-   (−)-3-(2-tetrahydrofuryl-methyl)-2-thioxanthine;-   3-n-butyl-2-thioxanthine;    and pharmaceutically acceptable salts thereof.

A further aspect of the invention is the use of the novel compounds offormula (Ia) or (Ib) as a medicament.

According to the invention, we further provide a process for thepreparation of the novel compounds of formula (Ia) or (Ib), or apharmaceutically acceptable salt, enantiomer, diastereomer or racematethereof which comprises:

(a) reaction of a compound of formula (IIa) or (IIb)

wherein R¹, R², R³ and R⁴ are as defined in formula (Ia) or (Ib), Xrepresents O or S and Y represents O;with a sulphurising compound such as Lawesson's reagent or phosphoruspentasulphide; to give a corresponding compound wherein Y represents S;or(b) reaction of a diamine of formula (IIIa) or (IIIb)

wherein R¹, R², R³, X and Y are as defined in formula (Ia) or (Ib);with formic acid or with a trialkylorthoester;and where necessary converting the resultant compound of formula (Ia) or(Ib), or another salt thereof, into a pharmaceutically acceptable saltthereof, or converting the resultant compound of formula (Ia) or (Ib)into a further compound of formula (Ia) or (Ib); and where desiredconverting the resultant compound of formula (Ia) or (Ib) into anoptical isomer thereof.

In process (a), a compound of formula (Ia) or (IIb) and a sulfurisingagent such as Lawesson's reagent, or phosphorus pentasulfide aredissolved or suspended in a suitable dry organic solvent such asbenzene, toluene, xylene, tetrahydrofuran, dichloromethane or dioxaneand then heated to between 30° C. and the reflux temperature of thesolvent until reaction is complete, typically for between one to 30hours. The reaction mixture is then cooled and filtered to removeinsoluble solids. The solvent is removed under reduced pressure and thecrude product is purified by column chromatography or byrecrystallisation.

In process (b), a diamine of formula (IIIa) or (IIIb) is treated at asuitable temperature with an excess of an appropriate ortho ester suchas triethylorthoformate, triethylorthoacetate, triethylorthopropionate,triethylorthobutanoate, tripropylorthoformate, tributylorthoformate andtriisopropylorthoformate, optionally in the presence of a suitablesolvent such as an alcohol, until reaction is complete. The temperatureis typically up to the reflux temperature of the reaction mixture, andreaction times are generally from 30 minutes to overnight. In oneembodiment, the orthoester is triethylorthoformate with ethanol as anoptional solvent.

Alternatively in process (b), a diamine of formula (IIIa) or (IIIb) istreated with 98% formic acid at a suitable temperature between ambienttemperature and the reflux temperature of the reaction mixture. Theprocess is continued for a suitable period of time, typically forbetween 0.5 to 5 hours. After removal of the formic acid, treatment witha suitable aqueous base, for example, with 10% aqueous sodium hydroxidesolution, then yields the compound of formula (I). The treatment withbase is carried out for a suitable time at a suitable temperature, forexample, for about 10 minutes to 4 hours at a temperature betweenambient temperature and the reflux temperature of the reaction mixture.

Other methods for the conversion of a diamine of formula (IIIa) or(IIIb) into a compound of formula (Ia) or (Ib) are described in theliterature and will be readily known to the person skilled in the art.

The present invention includes compounds of formula (Ia) or (Ib) in theform of salts, in particular acid addition salts. Suitable salts includethose formed with both organic and inorganic acids. Such acid additionsalts will normally be pharmaceutically acceptable although salts ofnon-pharmaceutically acceptable acids may be of utility in thepreparation and purification of the compound in question. Thus,preferred salts include those formed from hydrochloric, hydrobromic,sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic,succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids.

Salts of compounds of formula (Ia) or (Ib) may be formed by reacting thefree base, or a salt, enantiomer or racemate thereof, with one or moreequivalents of the appropriate acid. The reaction may be carried out ina solvent or medium in which the salt is insoluble or in a solvent inwhich the salt is soluble, for example, water, dioxan, ethanol,tetrahydrofuran or diethyl ether, or a mixture of solvents, which may beremoved in vacuo or by freeze drying. The reaction may also be ametathetical process or it may be carried out on an ion exchange resin.

Compounds of formulae (IIa) or (IIb) and compounds of formula (IIIa) or(IIIb) are either known in the literature or may be prepared using knownmethods that will be readily apparent to the man skilled in the art.

The compounds of the invention and intermediates thereto may be isolatedfrom their reaction mixtures and, if necessary further purified, byusing standard techniques.

The compounds of formula (Ia) or (Ib) may exist in enantiomeric forms.Therefore, all enantiomers, diastereomers, racemates and mixturesthereof are included within the scope of the invention. The variousoptical isomers may be isolated by separation of a racemic mixture ofthe compounds using conventional techniques, for example, fractionalcrystallisation, or HPLC. Alternatively, the various optical isomers maybe prepared directly using optically active starting materials.

Intermediate compounds may also exist in enantiomeric forms and may beused as purified enantiomers, diastereomers, racemates or mixtures.

The compounds of formula (Ia) or (Ib), and their pharmaceuticallyacceptable salts are useful because they possess pharmacologicalactivity as inhibitors of the enzyme MPO.

The compounds of formulae (Ia) and (Ib) and their pharmaceuticallyacceptable salts are indicated for use in the treatment or prophylaxisof diseases or conditions in which modulation of the activity of theenzyme myeloperoxidase (MPO) is desirable. In particular, linkage of MPOactivity to disease has been implicated in neuroinflammatory diseases.Therefore the compounds of the present invention are particularlyindicated for use in the treatment of neuroinflammatory conditions ordisorders in mammals including man. Such conditions or disorders will bereadily apparent to the man skilled in the art.

Conditions or disorders that may be specifically mentioned includemultiple sclerosis, Alzheimer's disease, Parkinson's disease,amyotrophic lateral sclerosis and stroke, as well as other inflammatorydiseases or conditions such as asthma, chronic obstructive pulmonarydisease, cystic fibrosis, idiopathic pulmonary fibrosis, acuterespiratory distress syndrome, sinusitis, rhinitis, psoriasis,dermatitis, uveitis, gingivitis, atherosclerosis, inflammatory boweldisease, renal glomerular damage, liver fibrosis, sepsis, proctitis,rheumatoid arthritis, and inflammation associated with reperfusioninjury, spinal cord injury and tissuedamage/scarring/adhesion/rejection. Lung cancer has also been suggestedto be associated with high MPO levels. The compounds are also expectedto be useful in the treatment of pain.

Prophylaxis is expected to be particularly relevant to the treatment ofpersons who have suffered a previous episode of, or are otherwiseconsidered to be at increased risk of, the disease or condition inquestion. Persons at risk of developing a particular disease orcondition generally include those having a family history of the diseaseor condition, or those who have been identified by genetic testing orscreening to be particularly susceptible to developing the disease orcondition.

For the above mentioned therapeutic indications, the dosage administeredwill, of course, vary with the compound employed, the mode ofadministration and the treatment desired. However, in general,satisfactory results are obtained when the compounds are administered ata dosage of the solid form of between 1 mg and 2000 mg per day.

The compounds of formulae (Ia) or (Ib), and pharmaceutically acceptablederivatives thereof, may be used on their own, or in the form ofappropriate pharmaceutical compositions in which the compound orderivative is in admixture with a pharmaceutically acceptable adjuvant,diluent or carrier. Thus, another aspect of the invention concerns apharmaceutical composition comprising a novel compound of formula (Ia)or (Ib), or a pharmaceutically acceptable salt thereof, in admixturewith a pharmaceutically acceptable adjuvant, diluent or carrier.Administration may be by, but is not limited to, enteral (includingoral, sublingual or rectal), intranasal, inhalation, intravenous,topical or other parenteral routes. Conventional procedures for theselection and preparation of suitable pharmaceutical formulations aredescribed in, for example, “Pharmaceuticals—The Science of Dosage FormDesigns”, M. E. Aulton, Churchill Livingstone, 1988. The pharmaceuticalcomposition preferably comprises less than 80% and more preferably lessthan 50% of a compound of formulae (Ia) or (Ib), or a pharmaceuticallyacceptable salt thereof.

There is also provided a process for the preparation of such apharmaceutical composition which comprises mixing the ingredients.

The invention is illustrated, but in no way limited, by the followingexamples:

¹H and ¹³C NMR spectra were recorded either on a 300 MHz Bruker DPXinstrument or on a Varian Unity 400 MHz spectrometer at 25° C. Thefollowing reference signals were used: the middle line of DMSO-d₆ δ 39.5(¹³C); DMSO-d₆ δ 2.50 (¹H). All mass spectra were recorded on a WatersLCMS (2790) instrument. Thin layer chromatography (TLC) was performed onMerck TLC aluminium sheets silica gel 60 F₂₅₄ pre-coated sheets (layerthickness 0.2 mm). Merck Silica gel 60 (0.063-0.200 mm) was used forcolumn chromatography. HPLC analysis were performed on a Gynkotek P580HPG, gradient pump with a Gynkotek UVD 170S UV-vis detector. Column;Waters symmetry C18, 5 μm, 3.9×150 mm. Preparative liquid chromatographywas performed on a Gynkotek P580 HPG, gradient pump with a Gynkotek UVD170S UV-vis detector. Column; Waters symmetry C18, 5 μm, 19×100 mm.

Starting materials were prepared according to the following references:

-   1. Merlos, M.; Gomez, L.; Vericat, M. L.; Bartroli, J.;    Garcia-Rafanell, J.; Form, J.; Eur. J. Med. Chem. Chim. Ther.; 25;    8; 1990; 653-658.-   2. Kjellin, P. G.; Persson, C. G. A., EP 0 010 531.-   3. Katritzky, A. R.; Drewniak, M., Tet. Lett. (1988), 29(15),    1755-1758.-   4. Van der Goot, H.; Schepers, M. J. P.; Sterk, G. J.; Timmerman,    H., Eur. J. Med. Chem. (1992), 27 (5), 511-517.

EXAMPLE 1 13-Diisobutyl-8-methyl-6-thioxanthine

1,3-Diisobutyl-8-methyl-xanthine¹ (0.20 g, 0.72 mmol) and Lawesson'sreagent (1.5 g, 3.6 mmol) were suspended in toluene (8 mL) and thenheated at 100° C. for 21 h. The reaction mixture was cooled and filteredto remove insoluble solids. The solvent was removed under reducedpressure and the crude product was purified by column chromatographyusing silica gel and eluting with ethyl acetate/heptane (1:1) giving thetitle compound (90 mg, 43% yield).

¹H NMR (DMSO-d₆): δ 13.1 (s, 1H), 4.28 (d, 2H, J 7.2 Hz), 3.84 (d, 2H, J7.5 Hz), 2.40 (s, 3H), 2.28-2.35 (m, 1H), 2.17-2.25 (m, 1H), 0.85-0.88(m, 12H).

MS (ES) ^(m)/z 295 (M+1).

EXAMPLE 2 1,3-Dibutyl-8-methyl-6-thioxanthine

1,3-Dibutyl-8-methyl-xanthine¹ (0.20 g, 0.72 mmol) and Lawesson'sreagent (0.87 g, 2.2 mmol) were suspended in toluene (8 mL) and heatedat 120° C. for 30 h. The resulting brown mixture was cooled and thesolvent evaporated under reduced pressure. The brownish solid residuewas suspended in 10% sodium hydroxide (25 mL) and stirred overnight.Then the pH of the solution was adjusted to pH 4 with 10% acetic acid.The precipitate was collected by filtration and washed with water. Thiscrude product was purified by column chromatography using silica gel andelution with ethyl acetate/heptane (9:1) giving the title compound (0.15g, 69% yield).

¹H NMR (DMSO-d₆): δ 13.1 (s, 1H), 4.40 (t, 2H, J 7.6 Hz), 3.99 (t, 2H, J7.3 Hz), 2.40 (s, 3H), 1.57-1.69 (m, 4H), 1.28-1.35 (m, 4H), 0.88-0.93(m, 6H).

¹³C NMR (DMSO-d₆): δ 173.5, 154.2, 148.9, 143.2, 118.9, 45.61, 43.13,29.24, 28.37, 19.51, 19.31, 14.42, 13.60.

MS (ES) ^(m)/z 295 (M+1).

EXAMPLE 3 3-Isobutyl-1,8-dimethyl-6-thioxanthine

1,3-Isobutyl-1,8-dimethyl-xanthine¹ (0.150 g, 6.35 mmol, 1.0 eq.) andLawesson's reagent (0.128 g, 3.17 mmol, 0.5 eq.) were dissolved intoluene (10 mL) and the reaction mixture was heated to reflux for 3.5 h.The conversion was less than 10% according to HPLC. Lawesson's reagent(0.5 g) was added and the reaction mixture was heated to refluxovernight. The solvent was evaporated off and the remaining brown solidwas purified by preparative HPLC to give the title compound (78 mg,49%).

¹H NMR (DMSO-d₆): δ 13.16 (s, 1H), 3.92 (d, 2H), 3.77 (s, 3H), 2.50 (s,3H), 2.35 (m, 1H), 0.97 (d, 6H).

EXAMPLE 4 3-(2-Methylbutyl)-6-thioxanthine

3-(2-Methylbutyl)-xanthine² (3 g, 0.013 mol) and phosphorus pentasulfide(5 g, 0.025 mol) in dioxane (250 mL) were refluxed for 3 h. Almost 150mL dioxane was distilled off and the solution was cooled down. Water(100 mL) was added and the mixture was stirred at room temperature for 2h. 2N Sodium hydroxide (75 mL) was added, the solution was filtered andneutralized with 5N hydrochloric acid. The crude crystals were filteredoff and recrystallised from ethanol to yield the title compound (1.6 g,51%).

¹H NMR (DMSO-d₆): δ 13.53 (s, 1H), 12.32 (s, 1H), 8.11 (s, 1H), 3.85(dd, 1H, ²J 13.1 Hz, ³J 7.1 Hz), 3.78 (dd, 1H, ²J 13.1 Hz, ³J 8.1 Hz),2.00 (m, 1H), 1.36 (m, 1H), 1.14 (m, 1H), 0.87 (t, 3H, J 7.6), 0.82 (d,3H, J 6.6).

¹³C NMR (DMSO-d₆): δ 175.11, 149.19, 145.73, 143.62, 118.32, 48.11,32.93, 26.40, 16.57, 11.05.

EXAMPLE 5 3-Isobutyl-8-methyl-6-thioxanthine

3-Isobutyl-8-methyl-xanthine² (4.5 g, 0.02 mol) and phosphoruspentasulfide (8 g, 0.04 mol) in dioxane (400 mL) were refluxed for 5 h.Almost 200 mL dioxane was distilled off and the solution was cooleddown. Water (250 mL) was added and the mixture was stirred at roomtemperature for 2 h. 2N Sodium hydroxide (150 mL) was added, thesolution was filtered and neutralized with 5N hydrochloric acid, and thesolution was left overnight. The crude crystals were filtered off andwashed with water, giving the required product (4.3 g). A portion (2.3g) was recrystallised from acetic acid to give pure product (1.5 g, 31%overall).

¹H NMR (DMSO-d₆): δ 13.13 (s, 1H), 12.16 (s, 1H), 3.77 (d, 2H, J 8.1Hz), 2.38 (s, 3H), 2.20 (m, 1H), 0.86 (d, 3H, J 7.1).

¹³C NMR (DMSO-d₆): δ 173.19, 154.23, 149.14, 146.11, 118.56, 49.29,26.63, 19.73, 14.54.

EXAMPLE 6 3-Isobutyl-2-thioxanthine a)6-Amino-1-isobutyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

Isobutylthiourea³ (3.8 g, 29 mmol) and ethyl cyanoacetate (3.9 g, 34mmol) were added to a solution of sodium ethoxide [made from sodium(0.72 g, 32 mmol) and absolute ethanol (30 mL)]. The resulting mixturewas refluxed for 4 h. After cooling to room temperature, the solvent wasevaporated under reduced pressure. 10% Acetic acid (45 mL) was added tothe viscous syrup. The resulting precipitate was collected by filtrationand the solid was washed with water. Recrystallisation frommethanol/water gave the desired product (4.0 g, 70%).

¹H NMR (DMSO-d₆): δ 11.8 (s, 1H), 6.99 (s, 2H), 4.85 (m, 2H), 4.61(broad s, 1H), 2.29 (m, 1H), 0.87 (d, 6H, J 6.6 Hz).

MS (ES) ^(m)/z 200 (M+1).

b) 6-Amino-1-isobutyl-5-nitroso-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

6-Amino-1-isobutyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (1.0 g, 5.0mmol) was suspended in 10% acetic acid (20 mL). Sodium nitrite (0.38 g,5.5 mmol) was added and the resulting mixture was heated at 75° C. for 1h. The reaction mixture became first pink and then purple. The purplemixture was cooled to room temperature. Then water (20 mL) was added andthe purple solid was collected by filtration and washed with water togive the title compound (1.1 g, 92% yield). This solid was used in thefollowing step without further purification.

¹H NMR (DMSO-d₆): δ 13.1 (broad s, 1H), 12.8 (broad s, 1H), 9.1 (broads, 1H), 4.80 (broad s, 1H), 3.78 (broad s, 1H), 2.21 (m, 1H), 0.88 (d,6H, J 6.3 Hz).

MS (ES) ^(m)/z 229 (M+1).

c) δ 6-Diamino-1-isobutyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

6-Amino-1-isobutyl-5-nitroso-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one(1.1 g, 4.5 mmol) was suspended in 32% aqueous ammonia (10 mL) and water(10 mL) was added. This red mixture was heated at 75° C. Sodiumdithionite was added in small portions. When 1.8 g (10 mmol) ofdithionite had been added the colour of the solution had changed fromred to pale yellow. At this point, all solid was dissolved. Afterheating for another 5 minutes a precipitate was formed in the solution.The reaction mixture was removed from the oil bath and stirred atambient temperature for 45 minutes. The pH of the solution was adjustedto neutral pH with 10% acetic acid. The yellow precipitate was collectedby filtration and washed with water and dried to yield the diamine (0.76g, 77%). This product was used without further purification.

¹H NMR (DMSO-d₆): δ 11.3 (broad s, 1H), 6.19 (s, 2H), 4.94 (broad s,1H), 3.70 (broad s, 1H), 3.43 (s, 2H), 2.27-2.35 (m, 1H), 0.88 (d, 6H, J6.1 Hz).

MS (ES) ^(m)/z 215 (M+1).

d) 3-Isobutyl-2-thioxanthine

5,6-Diamino-1-isobutyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.22 g,1.0 mmol) was suspended in formic acid (1.5 mL) and this solution washeated at 100° C. for 1 h. Excess formic acid was evaporated off underreduced pressure. 10% Sodium hydroxide (1.5 mL) was added to the orangesolid and the resulting solution was heated at 100° C. for 15 minutes.Water was added and the pH of the solution adjusted to pH 4 with diluteacetic acid. The resulting slurry was stirred for 0.5 h at ambienttemperature, then the precipitate was collected by filtration and washedwith water. Yield: (0.21 g, 90%).

¹H NMR (DMSO-d₆): δ 13.82 (s, 1H), 12.42 (s, 1H), 8.15 (s, 1H), 4.31 (d,2H, J 7.6 Hz), 2.50 (m, 1H), 0.88 (d, 6H, J 6.6 Hz).

¹³C NMR (DMSO-d₆): δ 173.81, 152.57, 149.79, 141.19, 110.68, 54.04,26.11, 19.79.

MS (ES) ^(m)/z 225 (M+1).

EXAMPLE 7 3-Isobutyl-2,6-dithioxanthine

3-Isobutyl-2-thioxanthine (0.20 g, 0.89 mmol) and Lawesson's reagent(1.1 g, 2.7 mmol) were suspended in toluene (8 mL). This mixture washeated at 120° C. for 17 h. The reaction mixture was cooled and thesolvent removed under reduced pressure. 10% Sodium hydroxide (20 mL) wasadded and the mixture stirred for 10 minutes. This solution was filteredto remove insoluble solids and the solid washed with 10% sodiumhydroxide solution. The basic filtrate was treated with dilute aceticacid until pH 4 was reached. The resulting precipitate was collected byfiltration and washed with water. Drying of the substance afforded thetitle compound (0.16 g, 73%).

¹H NMR (DMSO-d₆): δ 13.9 (s broad, 1H), 13.5 (s broad, 1H), 8.27 (s,1H), 4.32 (d, 2H, J 7.5 Hz), 2.48-2.55 (m, 1H), 0.89 (d, 6H, J 6.7 Hz).

¹³C NMR (DMSO-d₆): δ 173.3, 172.0, 144.9, 144.5, 122.8, 54.9, 26.3,20.2.

MS (ES) ^(m)/z 241 (M+1).

EXAMPLE 8 3-Isobutyl-8-methyl-2-thioxanthine

A mixture of5,6-diamino-1-isobutyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (Example6 (c), 0.70 g, 3.26 mmol) and triethylorthoacetate (10 mL) was heated at130° C. for 2 h and 40 minutes. Then the reaction mixture was cooled onan ice-bath, the solid filtered off and washed with ethanol (4×2 mL).The solid was dried in vacuo yielding the title compound (0.71 g, 95%).

¹H NMR (DMSO-d₆): δ 13.45 (s, 1H), 12.33 (s, 1H), 4.28 (d, 2H, J 7.6Hz), 2.50 (m, 1H), 2.39 (s, 3H), 0.87 (d, 6H, J 6.6 Hz).

¹³C NMR (DMSO-d₆): δ 173.47, 152.09, 151.18, 150.01, 110.62, 53.96,26.08, 19.75, 14.41.

MS (ES) ^(m)/z 239 (M+1).

EXAMPLE 9 3-Isobutyl-7-methyl-2-thioxanthine a)N-(6-Amino-1-isobutyl-4-oxo-2-thioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-formamide

5,6-Diamino-1-isobutyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (Example6 (c), 0.25 g, 1.2 mmol) was dissolved in formic acid (1.5 mL) andstirred at ambient temperature for 0.5 h. A pink precipitate started toform after a few minutes. Water was added and the resulting mixturestirred for 10 minutes. The pink solid was collected by filtration,washed with water and dried to yield the title compound (0.25 g, 86%).This material was used without further purification. NMR showed that theproduct was obtained as a mixture of two tautomers: formamide (major)and imino (minor).

¹H NMR (DMSO-d₆): δ 12.0 (broad s, 1H), 8.73 (s, 1H), 8.07 (s, 1H), 6.85(s, 2H), 4.94 (broad s, 1H), 3.71 (broad s, 1H), 2.22-2.32 (m, 1H), 0.88(d, 6H, J 6.5 Hz). Additional peaks arising from the imino isomer: 8.12(d, 1H, J 11.5 Hz), 7.77 (d, 1H, J 11.5 Hz), 7.13 (s, 2H).

MS (ES) ^(m)/z 243 (M+1).

b)6-Amino-1-isobutyl-5-methylamino-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

N-(6-Amino-1-isobutyl-4-oxo-2-thioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-formamide(0.25 g, 1.0 mmol) was suspended in dry tetrahydrofuran (5 mL) andborane.dimethylsulphide complex (1M in dichloromethane, 2.5 mL, 2.5mmol) was added dropwise. The reaction mixture was stirred at ambienttemperature for 2.5 h. To the resulting clear yellow solution was addeda few drops of 2M hydrochloric acid to eliminate unreacted borane. Waterwas added and the resulting aqueous solution was extracted withdichloromethane (3×15 mL). The combined organic phase was washed withbrine and dried over Na₂SO₄. The solvent was evaporated off underreduced pressure yielding the title compound (0.12 g, 54% yield). Thismaterial was used without further purification.

¹H NMR (DMSO-d₆): δ 11.9 (broad s, 1H), 5.75 (s, 2H), 4.94 (broad s,1H), 3.70 (broad s, 1H), 3.43 (s, 2H), 2.38 (s, 3H), 2.24-2.32 (m, 1H),0.87 (d, 6H, J 6.8 Hz).

MS (ES) ^(m)/z 229 (M+1).

c) 3-Isobutyl-7-methyl-2-thioxanthine

6-Amino-1-isobutyl-5-methylamino-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one(0.11 g, 0.48 mmol) was dissolved in formic acid (1 mL) and heated at85° C. for 1 h. The excess of formic acid was evaporated off underreduced pressure. 10% Sodium hydroxide solution (2 mL) was added and thesolution was heated at 85° C. for 20 minutes. Water was added and the pHwas adjusted to 4 with dilute acetic acid, upon which a white solidprecipitated. The white solid was collected by filtration, washed withwater and dried to yield the title compound (85 mg, 74%).

¹H NMR (DMSO-d₆): δ 12.4 (s, 1H), 8.10 (s, 1H), 4.28 (d, 2H, J 7.5 Hz),3.89 (s, 3H), 2.44-2.50 (m, 1H), 0.88 (d, 6H, J 6.7 Hz).

¹³C NMR (DMSO-d₆): δ 174.3, 153.2, 150.1, 143.7, 111.2, 54.1, 33.6,26.4, 20.1.

MS (ES) ^(m)/z 239 (M+1).

EXAMPLE 10 3-Cyclohexylmethyl-2-thioxanthine a)6-Amino-1-cyclohexylmethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The title compound was prepared in accordance with the general method ofExample 6 (a) using cyclohexylmethylthiourea⁴ (3.92 g, 22.7 mmol),yielding the title compound as a white solid (4.87 g, 90%).

¹H NMR (DMSO-d₆): δ 11.75 (s, 1H), 6.93 (s, 2H), 5.1-4.7 (br m, 1H),4.83 (s, 1H), 3.55 (broad, 1H), 1.93 (br, 1H), 1.75-1.30 (br m, 5H),1.10 (br, 5H).

b)6-Amino-1-cyclohexymethyl-5-nitroso-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The title compound was prepared in accordance with the general method inExample 6 (b) from6-amino-1-cyclohexylmethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (3.75g, 15.7 mmol), yielding 3.60 g (85%) of the product as a purple solid.

¹H NMR: δ 13.5 (br s, 1H), 12.7 (br s, 1H), 9.1 (br s, 1H), 4.84 (br s,1H), 3.82 (br s, 1H), 1.80 (br, 1H), 1.64-1.59 (br m, 5H), 1.07 (br,5H).

c) δ6-Diamino-1-cyclohexylmethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The title compound was prepared in accordance with the general method inExample 6 (c) from6-amino-1-cyclohexylmethyl-5-nitroso-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one(3.60 g, 13.4 mmol) and was used without purification in the next step.

¹H NMR (DMSO-d₆): δ 6.17 (s, 2H), 5.01 (br, 1H), 4.0-3.0 (very broad,3H), 1.97 (br, 1H), 1.8-1.3 (br m, 5H), 1.09 (br m, 5H).

d) 3-Cyclohexylmethyl-2-thioxanthine

5,6-Diamino-1-cyclohexylmethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one,(1.44 g, 5.67 mmol) together with triethyl orthoformate (15 mL) washeated at 146° C. for 2 h and 10 minutes. The mixture was allowed tocool to ambient temperature and then further cooled on an ice-bath,followed by addition of heptane (5 mL). After filtration of thesuspension and washing with heptane (20 mL), the obtained solid wasdried in vacuo. Suspending the solid (1.2 g) in a hot mixture of2-propanol (125 mL), water (5 mL) and tert-butyl methyl ether (25 mL)gave, after cooling and filtration, a white precipitate which was washedwith further tert-butyl methyl ether (5 mL). The solid was dried invacuo to give the title compound (0.95 g, 63%).

¹H NMR (DMSO-d₆): δ 13.69 (s, 1H), 12.35 (s, 1H), 8.12 (s, 1H), 4.33 (d,2H, J 7.1 Hz), 2.18 (m, 1H), 1.49-1.50 (m, 5H), 1.02-1.17 (m, 5H).

¹³C NMR (DMSO-d₆): δ 173.65, 152.68, 149.90, 141.41, 110.96, 52.97,35.31, 30.09, 25.88, 25.32.

MS (ES) ^(m)/z 265 (M+1).

EXAMPLE 11 3-(3-Methoxypropyl)-2-thioxanthine a)6-Amino-1-(3-methoxypropyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

Sodium methoxide (0.81 g, 21.2 mmol, 1.05 eq.) was added to a solutionof 3-methoxypropylthiourea (3.00 g, 20.2 mmol) in ethanol (10 mL). Ethylcyanoacetate (2.18 mL, 20.2 mmol) in ethanol (10 mL) was added and theresulting white slurry was heated to reflux for 2.5 h. The solvent wasevaporated and the remaining pale brown oil was treated with 2M aceticacid (15 mL). The white crystals were filtered off and washed withacetic acid to give the title compound (2.10 g, 48%).

¹H NMR (DMSO-d₆): δ 1.77 (s, 1H), 6.95 (s, 2H), 4.86 (s, 1H), 3.39 (t,2H), 3.24 (s, 3H), 1.88 (m, 2H).

b) 3-(3-Methoxypropyl)-2-thioxanthine

Acetic acid (25 mL) was added to6-amino-1-(3-methoxypropyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one(2.00 g, 9.29 mmol) and the red reaction mixture was heated to 90° C.Sodium nitrite (0.71 g, 10.2 mmol) in water (7 mL) was added, the oilbath was removed and the reaction mixture was stirred for 20 minutes.The solvents were co-evaporated with ethanol and the remaining red solid(1.8 g, 79%) was used in the next step without further purification.

Platinum on carbon (0.5 g) was added to a solution of the crude6-amino-1-(3-methoxypropyl)-5-nitroso2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (1.80 g, 7.38 mmol) intetrahydrofuran (80 mL) and water (20 mL) and the reaction mixture washydrogenated at atmospheric pressure for 2 h. The catalyst was filteredoff and the pale brown filtrate was co-evaporated with ethanol (250 mL).The resulting brown solid, 1.6 g, was used in the next step withoutfurther purification.

5,6-Diamino-1-cyclohexylmethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one(1.6 g, 12.2 mmol) was dissolved in ethanol (10 mL) and triethylorthoformate (10 mL) and the reaction mixture was refluxed for 2.5 h.The solvents were evaporated off and the resulting brown solid waspurified by flash chromatography (heptane/ethyl acetate, 4:1-1:1) togive the title compound (110 mg, 9%).

¹H NMR (DMSO-d₆): δ 13.78 (s, 1H), 12.40 (s, 1H), 8.16 (s, 1H), 4.52 (t,2H, J 7.1 Hz), 3.41 (t, 2H, J 7.1 Hz), 3.21 (s, 3H), 1.98 (m, 2H).

¹³C NMR (DMSO-d₆): δ 173.27, 152.63, 149.30, 141.50, 110.94, 69.51,57.82, 45.47, 26.68.

EXAMPLE 12 3-Cyclopropylmethyl-2-thioxanthine a)6-Amino-1-cyclopropylmethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

To 1-cyclopropylmethyl-2-thiourea (0.60 g, 4.6 mmol) in ethanol (10 mL)was added sodium methoxide (0.26 g, 4.8 mmol) and, after 5 minutes,ethyl cyanoacetate (0.50 mL, 4.6 mmol). The resulting mixture was heatedto reflux for 2 h and 40 minutes followed by evaporation of the solventunder reduced pressure and treatment of the resulting yellow solid with2M aqueous acetic acid (10 mL) giving a white solid. The solid wascollected by filtration and washed with 2M aqueous acetic acid (10 mL),stirred with ethanol (10 mL) followed by evaporation and drying underreduced pressure, giving the title compound (0.51 g, 56%).

MS (ES) ^(m)/z 198 (M+1).

b) 3-Cyclopropylmethyl-2-thioxanthine

6-Amino-1-cyclopropylmethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one(0.50 g, 2.5 mmol) was suspended in acetic acid (8 mL) and, afterheating at 90° C. for 15 minutes, sodium nitrite (0.19 g, 2.8 mmol) inwater (1 mL) was added to the solution. After 15 minutes the heating wasremoved and the reaction mixture stirred at ambient temperature for 3 h.Ethanol (30 mL) was added and the solvents were removed under reducedpressure. The resulting oil was treated with ethanol (30 mL) and thisafforded, upon evaporation and drying,6-amino-1-cyclopropylmethyl-5-nitroso-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one(0.61 g) as a red-brown solid.

The crude product (0.61 g) from the previous reaction was dissolved inwater (10 mL) and tetrahydrofuran (30 mL) and platinum on carbon (0.30g) were added. The mixture was subjected to hydrogenation at atmosphericpressure for 4 h, the catalyst was removed by filtration and thesolvents were removed under reduced pressure. Evaporation of addedethanol (50 mL) afforded an orange solid. The residue was dissolved inethanol (10 mL) and triethyl orthoformate (5 mL) was added and theresulting mixture was heated at reflux overnight. Evaporation of thesolvent and purification using preparative HPLC afforded the desiredcompound (38 mg, 6.2% yield from6-amino-1-cyclopropylmethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one).

¹H NMR (DMSO-d₆): δ 13.78 (s, 1H), 12.43 (s, 1H), 8.15 (s, 1H), 4.37 (d,2H, J 7.1 Hz), 1.50 (m, 1H), 0.52 (m, 2H), 0.45 (m, 2H).

¹³C NMR (DMSO-d₆): δ 173.52, 152.62, 149.52, 141.48, 111.02, 51.71,9.27, 3.50.

MS (ES) ^(m)/z 223 (M+1).

EXAMPLE 13 3-Isobutyl-1-methyl-2-thioxanthine a)1-isobutyl-3-methylthiourea

Methylamine (2M in methanol, 20.0 mL, 40.2 mmol) was added dropwise toisobutylisothiocyanate (2.00 mL, 16.5 mmol) during 15 minutes at roomtemperature. The reaction mixture was heated to reflux for 3.5 h and thesolvent was evaporated off to give the title compound (2.37 g, 98%) as acolourless oil.

¹H NMR (DMSO-d₆): δ 7.40 (s, 1H), 7.29 (s, 1H), 3.15 (broad s, 2H), 2.80(d, 2H), 1.81 (m, 1H), 0.83 (d, 6H).

b) 6-Amino-1-isobutyl-3-methyl-5-nitroso-2-thioxo-1H-pyrimidin-4-one

A solution of cyanoacetic acid (1.52 g, 17.8 mmol) in acetic anhydride(2.45 mL, 25.9 mmol) was added to 1-isobutyl-3-methylthiourea (2.37 g,16.2 mmol). The reaction mixture was heated to 60° C. for 1.5 h. Thesolvent was evaporated and the resulting red oil was redissolved inethanol (5 mL) and 5M sodium hydroxide (1.6 mL, 8.1 mmol) was added. Thereaction mixture was refluxed for 2 h. The solvent was co-evaporatedwith ethanol and the resulting pale brown solid was purified by flashchromatography (ethyl acetate) to yield6-amino-1-isobutyl-3-methyl-2-thioxo-1H-pyrimidin-4-one (1.0 g, 29%) asa yellow solid.

Sodium nitrite (0.34 g, 4.9 mmol) in water (1.5 mL) was added to asolution of the amine (1.00 g, 4.7 mmol) in ethanol (7.0 mL) at roomtemperature. 5M Hydrochloric acid (1.0 mL, 4.9 mmol) was added and theresulting dark red reaction mixture was stirred at room temperature for2 h. Ethanol (20 mL) was added and the red crystals were filtered offand washed with diethyl ether. Drying of the crystals gave the titlecompound (0.68 g, 60%).

¹H NMR (DMSO-d₆): δ 12.87 (s, 1H), 9.35 (s, 1H), 4.28 (dd, 2H), 3.75 (s,3H), 2.34 (m, 1H), 0.90 (d, 6H).

c) 3-Isobutyl-1-methyl-2-thioxanthine

Palladium on carbon (3.70 g) was added to a solution of6-amino-1-isobutyl-3-methyl-5-nitroso-2-thioxo-1H-pyrimidin-4-one (6.0g, 24.8 mmol) in tetrahydrofuran (1200 mL) and water (300 mL) and thereaction mixture was hydrogenated (2.5 bar) for 21 h. The catalyst wasfiltered off and the tetrahydrofuran was evaporated off under reducedpressure. The residue was extracted with ethyl acetate (3×200 mL). Theorganic phase was concentrated and ethanol (100 mL) was added to theresidue and evaporated.

The brown diamine intermediate was dissolved in triethyl orthoformate(50 mL) and the reaction mixture was heated to 140° C. for 40 minutes.The reaction mixture was concentrated and co-evaporation with ethanolafforded a brown solid. The residue was purified by flash chromatography(heptane/ethyl acetate, 2:1-ethyl acetate) followed by washing of thesolid with diethyl ether and hexane to give the title compound (160 mg,2.7%).

¹H NMR (DMSO-d₆): δ 13.86 (s, 1H), 8.21 (s, 1H), 4.34 (d, 2H, J 7.1 Hz),3.89 (s, 3H), 2.40 (m, 1H), 0.86 (d, 6H, J 7.1 Hz).

¹³C NMR (DMSO-d₆): δ 174.68, 153.33, 148.41, 141.73, 109.92, 52.83,37.17, 25.77, 19.92.

EXAMPLE 14 3-(2-Tetrahydrofuryl-methyl)-2-thioxanthine a)6-Amino-1-(2-tetrahydrofuryl-methyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

2-Tetrahydrofuryl-methyl-thiourea (1.0 g, 6.2 mmol) and ethylcyanoacetate (0.85 g, 7.5 mmol) were added to a solution of sodiumethoxide [freshly made from sodium (0.16 g, 6.9 mmol) and absoluteethanol (4 mL)]. The resulting mixture was refluxed for 3.5 h. Aftercooling to room temperature, the solvent was evaporated under reducedpressure, and the resulting viscous syrup was re-dissolved in water (30mL). This basic solution was neutralized with 2M hydrochloric acid. Theresulting precipitate was collected by filtration and the solid waswashed with water. This crude product (1.3 g, 90%) was used withoutfurther purification.

¹H NMR (DMSO-d₆): δ 11.9 (s, 1H), 6.79 (s, 2H), 4.91 (s, 1H), 4.62-4.65(m, 1H), 4.21-4.31 (m, 3H), 3.81-3.87 (m, 1H), 3.63-3.68 (m, 1H),1.77-2.01 (m, 3H), 1.57-1.65 (m, 1H).

MS (ES) ^(m)/z 228 (M+1).

b)6-Amino-1-(2-tetrahydrofuryl-methyl)-5-nitroso-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

6-Amino-1-(2-tetrahydrofuryl-methyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one(1.3 g, 5.6 mmol) was suspended in 10% aqueous acetic acid (25 mL).Sodium nitrite (0.43 g, 6.2 mmol) was added and this mixture was heatedat 75° C. for 1 h. The purple solid was collected by filtration, washedand dried, giving the title product (1.3 g, 90%).

¹H NMR: δ 13.3 (br s, 1H), 12.8 (br s, 1H), 8.93 (br s, 1H), 4.57 (br s,1H), 4.45 (br s, 1H), 4.18-4.24 (m, 1H), 3.74-3.79 (m, 1H), 3.59-3.64(m, 1H), 1.86-2.01 (m, 2H), 1.74-1.82 (m, 1H), 1.59-1.67 (m, 1H).

c) δ6-Diamino-1-(2-tetrahydrofuryl-methyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

6-Amino-1-(2-tetrahydrofuryl-methyl)-5-nitroso-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one(1.3 g, 5.1 mmol) was dissolved in 32% aqueous ammonia (15 mL) and water(15 mL) was added. The red solution was heated at 70° C. while sodiumdithionite (2.2 g, 13 mmol) was added in small portions. Heating wascontinued for another 15 minutes and then the yellow solution wasstirred at ambient temperature for 1 h. The solution was neutralizedwith 2M hydrochloric acid. The yellow precipitate was collected byfiltration, washed with water, and dried, giving the title product (0.90g, 73%). This material was used in the next step without furtherpurification.

¹H NMR (DMSO-d₆): δ 5.96 (s, 2H), 4.74 (br d, 1H), 4.35 (br s, 1H),4.21-4.28 (m, 1H), 3.84-3.89 (m, 1H), 3.64-3.69 (m, 1H), 3.49 (br s,2H), 1.78-2.01 (m, 4H), 1.60-1.67 (1H).

MS (ES) ^(m)/z 243 (M+1).

d) 3-(2-Tetrahydrofuryl-methyl)-2-thioxanthine

5,6-Diamino-1-(2-tetrahydrofuryl-methyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.25 g, 1.0 mmol)was dissolved in formic acid (1 mL) and heated at 70° C. for 0.5 h.After a few minutes a pink solid formed in the solution. The excess offormic acid was evaporated off and the resulting solid dissolved in 10%sodium hydroxide solution (4 mL). This solution was heated at 70° C. for40 minutes, then neutralized with 2M hydrochloric acid. The resultingprecipitate was collected by filtration, washed with water and dried,giving pure product (0.23 g, 87%).

¹H NMR (DMSO-d₆): δ 13.8 (br s, 1H), 12.4 (br s, 1H), 8.16 (s, 1H),4.53-4.61 (m, 2H), 4.38-4.44 (m, 1H), 3.79-3.84 (m, 1H), 3.58-3.63 (m,1H), 1.72-1.98 (m, 4H).

¹³C NMR (DMSO-d₆): δ 173.65, 152.68, 149.90, 141.41, 110.96, 52.97,35.31, 30.09, 25.88, 25.32.

MS (ES) ^(m)/z 253 (M+1).

EXAMPLE 15 3-(2-Methoxy-ethyl)-2-thioxanthine a)6-Amino-1-(2-methoxy-ethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The title compound was prepared in accordance with the general method ofExample 14 (a) but using (2-methoxy-ethyl)-thiourea (1.5 g, 11 mmol),yielding the title compound as a white solid (2.1 g, 93%).

¹H NMR (DMSO-d₆): δ 11.9 (s, 1H), 6.82 (s, 2H), 4.89 (s, 1H), 4.53(broad s, 2H), 3.62 (t, 2H, J=5.9 Hz), 3.29 (s, 3H).

MS (ES) ^(m)/z 202 (M+1).

b)6-Amino-1-(2-methoxy-ethyl)-5-nitroso-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

6-Amino-1-(2-methoxy-ethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (1.0g, 5.0 mmol) was suspended in 10% acetic acid (20 mL). Sodium nitrite(0.38 g, 5.5 mmol) was added and the resulting mixture was heated at 75°C. for 1 h. The reaction mixture became first pink and then purple.Water (20 mL) was added and the reaction mixture was put in the fridgeovernight. The purple solid was collected by filtration and washed withwater to give the title compound (0.42 g, 37%). A second crop of product(0.22 g, 19%) was obtained by reducing the volume of the purplefiltrate. The crude product was used in the following step withoutfurther purification.

¹H NMR (DMSO-d₆): δ 13.4 (br s, 1H), 12.8 (br s, 1H), 9.06 (br s, 1H),4.54 (br s, 2H), 3.60 (t, 2H, J 5.8 Hz), 3.24 (s, 3H).

c) δ6-Diamino-1-(2-methoxy-ethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The title compound was prepared in accordance with the general method ofExample 14 (c) but using6-amino-1-(2-methoxy-ethyl)-5-nitroso-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one(0.42 g, 1.8 mmol), yielding the title compound as a yellow solid (0.28g, 68%).

¹H NMR (DMSO-d₆): δ 11.9 (br s, 1H), 5.94 (s, 2H), 4.58 (br s, 2H), 3.64(t, 2H, J 5.6 Hz), 3.47 (br s, 2H), 3.28 (s, 3H).

MS (ES) ^(m)/z 217 (M+1).

d) 3-(2-Methoxy-ethyl)-2-thioxanthine

5,6-Diamino-1-(2-methoxy-ethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one(0.27 g, 1.3 mmol) was suspended in formic acid (2 mL) and this solutionwas heated at 90° C. for 1.5 h. Excess formic acid was evaporated offunder reduced pressure. 10% Sodium hydroxide solution (5 mL) was addedto the orange solid and the resulting solution was heated at 90° C. for2 h. The reaction mixture was neutralized with dilute acetic acid. Theresulting solution was put in the fridge for several days, then theorange needle-like crystals that had formed were collected by filtrationand washed with water. Yield: (0.11 g, 40%).

¹H NMR (DMSO-d₆): δ 13.8 (broad s, 1H), 12.5 (broad s, 1H), 8.16 (s,1H), 4.65 (t, 2H, J 6.4 Hz), 3.73 (t, 2H, J 6.4 Hz), 3.28 (s, 3H).

¹³C NMR (DMSO-d₆): δ 172.14, 151.06, 148.02, 139.85, 109.20, 66.04,56.65, 44.72.

MS (ES) ^(m)/z 227 (M+1).

EXAMPLE 16 3-(3-(1-Morpholinyl)-propyl)-2-thioxanthine a)6-Amino-1-(3-(1-morpholinyl)-propyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The title compound was prepared in accordance with the general method ofExample 14 (a) but using 1-(3-(1-morpholinyl)-propyl)-2-thiourea (1.1 g,5.3 mmol), yielding the title compound as a white solid (1.2 g, 87%).

¹H NMR (DMSO-d₆): δ 11.8 (s, 1H), 7.24 (s, 2H), 4.84 (s, 1H), 4.33 (brs, 2H), 3.55-3.57 (m, 4H), 2.30-2.36 (m, 6H), 1.82-1.89 (m, 2H).

MS (ES) ^(m)/z 271 (M+1).

c) δ6-Diamino-1-(3-(1-morpholinyl)-propyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

6-Amino-1-(3-(1-morpholinyl)-propyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one(0.57 g, 2.1 mmol) was dissolved in 10% acetic acid (10 mL). Sodiumnitrite (0.16 g, 2.3 mmol) was added and the slurry was stirred atambient temperature. After 2 h there was still a lot of startingmaterial left. More sodium nitrite (0.32 g, 4.6 mmol) was added and thesolution stirred overnight. The precipitate was collected by filtrationand washed with water. This extremely insoluble solid was reducedwithout analysis. The solid was dissolved in 32% aqueous ammonia (6 mL)and then water (6 mL) was added. The resulting red solution was heatedat 70° C. and sodium dithionite (0.91 g, 5.2 mmol) was added in smallportions. Then the solution was stirred at 70° C. for 1.5 h. More sodiumdithionite (0.91 g, 5.2 mmol) was added and the solution stirred at 70°C. for another 2.5 h. The neutral solution was filtered to removeinsoluble solid. The filtrate was concentrated and the resulting yellowsolid suspended in water. The solid was collected by filtration, washedwith water, and dried to yield the title product (0.068 g, 11%).

¹H NMR: δ 12.0 (br s, 1H), 6.48 (s, 2H), 3.59 (m, 4H), 2.30-2.45 (m,6H), 1.88-1.91 (m, 2H).

MS (ES) ^(m)/z 286 (M+1).

d) 3-(3-(1-Morpholinyl)-propyl)-2-thioxanthine

5,6-Diamino-1-(3-(1-morpholinyl)-propyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one(0.068 g, 0.24 mmol) was dissolved in formic acid (0.4 mL) and stirredat ambient temperature for 1 h. The excess of formic acid was evaporatedoff and 10% sodium hydroxide solution (1.5 mL) was added and the yellowsolution was heated at 70° C. for 40 minutes. The cooled solution wasneutralized with 2M hydrochloric acid and put into the fridge forseveral hours. The precipitate was collected by filtration, washed withwater, and dried yielding the title compound as an off-white solid(0.025 g, 36%).

¹H NMR (DMSO-d₆): δ 13.7 (broad s, 1H), 12.4 (s, 1H), 8.17 (s, 1H), 4.53(t, 2H, J 7.5 Hz), 3.52 (m, 4H), 2.31-2.46 (m, 6H), 1.91-1.99 (m, 2H).

¹³C NMR (DMSO-d₆): δ 173.68, 152.99, 149.82, 141.75, 111.24, 66.39,55.70, 53.43, 46.58, 23.35.

MS (ES) ^(m)/z 296 (M+1).

EXAMPLE 17 3-(2-Furyl-methyl)-2-thioxanthine a)6-Amino-1-(2-furyl-methyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The title compound was prepared in accordance with the general method ofExample 14 (a) except that the reaction time was reduced to 1.5 h andthe product was precipitated with dilute acetic acid. Using2-furyl-methylthiourea (1.0 g, 6.4 mmol), the title product (0.95 g,66%) was obtained.

¹H NMR (DMSO-d₆): δ 11.8 (br s, 1H), 7.58-7.62 (m, 1H), 7.05 (br s, 2H),6.38-6.42 (m, 1H), 6.31-6.36 (m, 1H), 5.68 (br s, 2H), 4.85 (s, 1H).

MS (ES) ^(m)/z 224 (M+1).

b)6-Amino-1-(2-furyl-methyl)-5-nitroso-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The title compound was prepared in accordance with the general method ofExample 14 (b) except that the reaction mixture was first heated at 60°C. for 1 h and then stirred at ambient temperature for 1 h. The product(0.25 g, 60%) was obtained as a brown solid when6-amino-1-(2-furyl-methyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.37g, 1.6 mmol) and 2 equivalents of sodium nitrite (0.23 g, 3.3 mmol) wereused.

¹H NMR: δ 12.1 (br s, 1H), 7.54-7.57 (m, 1H), 7.45-7.47 (m, 1H),6.37-6.40 (m, 1H), 6.32-6.38 (m, 1H), 6.30-6.32 (m, 1H), 5.62 (s, 2H),5.48 (s, 2H).

c) δ6-Diamino-1-(2-furyl-methyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The title compound (0.12 g, 52%) was prepared in accordance with thegeneral method in Example 14 (c) starting from6-amino-1-(2-furyl-methyl)-5-nitroso-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one(0.25 g, 0.99 mmol), and was used without purification in the next step.

¹H NMR (DMSO-d₆): δ 12.5 (br s, 1H), 12.2 (s, 1H), 7.58-7.60 (m, 1H),7.55-7.57 (m, 1H), 6.38-6.41 (m, 2H), 6.34-6.37 (m, 1H), 6.30 (br s,2H), 5.77 (s, 2H), 5.63 (s, 2H).

MS (ES) ^(m)/z 239 (M+1).

d) 3-(2-Furyl-methyl)-2-thioxanthine

5,6-Diamino-1-(2-furyl-methyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one(0.12 g, 0.51 mmol) in formic acid (0.5 mL) was stirred at ambienttemperature for 0.5 h. The excess of formic acid was evaporated off andthe resulting solid dissolved in 10% sodium hydroxide solution (3 mL).This solution was heated at 70° C. for 0.5 h. The reaction mixture wasneutralized with 2M hydrochloric acid. The resulting precipitate wascollected by filtration, washed with water, and dried. Yield: (0.047 g,37%).

¹H NMR (DMSO-d₆): δ 13.9 (s, 1H), 12.5 (s, 1H), 8.18 (s, 1H), 7.55-7.57(m, 1H), 6.36-6.39 (m, 2H), 5.69 (s, 2H).

¹³C NMR (DMSO-d₆): δ 174.14, 152.85, 149.56, 149.33, 142.77, 141.80,110.93, 109.40, 44.26.

MS (ES) ^(m)/z 249 (M+1).

EXAMPLE 18 3-(4-Methoxybenzyl)-2-thioxanthine a)6-Amino-1-(4-methoxybenzyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The title compound was prepared according to the general method ofExample 14 (a) except that the reaction was conducted for 2.5 h atreflux temperature followed by 16 h at ambient temperature andprecipitation of the product was made using dilute acetic acid. Startingwith (4-methoxybenzyl)-thiourea (1.0 g, 5.1 mmol) afforded the desiredproduct. (1.2 g, 92%).

¹H NMR (CD₃OD): δ 7.19 (d, 2H, J 8.6 Hz), 6.89 (d, 2H, J 8.6 Hz), 5.72(br s, 2H), 5.06 (s, 1H), 3.77 (s, 3H).

MS (ES) ^(m)/z 264 (M+1).

b)6-Amino-1-(4-methoxybenzyl)-5-nitroso-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The title compound was prepared according to the general method ofExample 14 (b) but using a 2.5 h reaction time. Using6-amino-1-(4-methoxybenzyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (1.2g, 4.7 mmol) yielded the product (1.2 g, 88%) as a blue-green solid thatwas used in the subsequent reaction without further purification.

¹H NMR (DMSO-d₆): δ 11.9 (s, 1H), 7.18-7.12 (m, 2H), 6.95-6.83 (m, 2H),5.58 (br s, 2H), 3.70 (s, 3H).

c) δ6-Diamino-1-(4-methoxybenzyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The title compound was prepared according to the general method ofExample 14 (c) except that dilute acetic acid was used forneutralization of the reaction mixture. The desired product (0.83 g,73%) was prepared as a yellow solid starting from6-amino-1-(4-methoxybenzyl)-5-nitroso-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one(1.2 g, 4.1 mmol).

¹H NMR (DMSO-d₆): δ 11.7 (br s, 2H), 7.20-7.12 (m, 2H), 6.92-6.85 (m,2H), 6.06 (s, 2H), 5.73 (br s, 2H), 3.71 (s, 3H).

MS (ES) ^(m)/z 279 (M+1).

d) 3-(4-Methoxybenzyl)-2-thioxanthine

5,6-Diamino-1-(4-methoxybenzyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one(0.83 g, 3.0 mmol) was dissolved in formic acid (3.0 mL) and theresulting solution heated at 100° C. for 1 h. The excess formic acid wasremoved under reduced pressure and the residue dissolved in 10%potassium hydroxide solution (8 mL) and heated at 100° C. for 15minutes. The reaction mixture was neutralized with 10% acetic acid andthe resulting precipitate collected by filtration. The precipitate wasrecrystallised from ethanol: dimethylformamide and the isolated crystalsdissolved in 1M potassium hydroxide solution, precipitated byneutralization with 10% acetic acid and collected by filtration. Afterdrying, the title compound (0.14 g, 16%) was obtained.

¹H NMR (DMSO-d₆): δ 13.9 (br s, 1H), 12.5 (s, 1H), 8.15 (s, 1H), 7.36(d, 2H, J 8.6 Hz), 6.84 (d, 2H, J 8.9 Hz), 5.63 (s, 2H), 3.70 (s, 3H).

¹³C NMR (DMSO-d₆): δ 173.85, 158.52, 152.45, 149.36, 141.41, 129.35,127.97, 113.58, 110.83, 55.01, 49.63.

MS (ES) ^(m)/z 289 (M+1).

EXAMPLE 19 3-(4-Fluorobenzyl)-2-thioxanthine a)6-Amino-1-(4-fluorobenzyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The title compound was prepared according to the general method ofExample 14 (a) except that the reaction time was 16 h and precipitationof the product was made by treatment with dilute acetic acid.(4-Fluorobenzyl)-thiourea (1.0 g, 5.4 mmol) afforded the product (1.2 g,86%) as a white solid.

¹H NMR (DMSO-d₆): δ 11.9 (br s, 1H), 7.27-7.11 (m, 4H), 6.91 (s, 2H),5.67 (br s, 2H), 4.89 (s, 1H).

MS (ES) ^(m)/z 252 (M+1).

b)6-Amino-1-(4-fluorobenzyl)-5-nitroso-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The title compound was prepared according to the general method ofExample 14 (b) except increasing the reaction time to a total of 8 h.6-Amino-1-(4-fluorobenzyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (1.2g, 4.7 mmol) afforded the desired product (0.88 g, 67%).

¹H NMR (DMSO-d₆): δ 13.1 (br s, 1H), 12.8 (br s, 1H), 7.33-7.08 (m, 2H),7.13 (t, 2H, J 8.7 Hz), 5.62 (br s, 2H).

c) δ6-Diamino-1-(4-fluorobenzyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The title compound was prepared in accordance with the general method ofExample 14 (c) except that the reaction was kept at 75° C. for 1 hfollowed by 20 minutes at ambient temperature and neutralization of thereaction mixture was made with dilute acetic acid. Using6-amino-1-(4-fluorobenzyl)-5-nitroso-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one(0.88 g, 3.1 mmol) gave the desired product (0.55 g, 66%).

¹H NMR (DMSO-d₆): δ 12.1 (br s, 2H), 7.29-7.12 (m, 4H), 6.08 (s, 2H),5.75 (br s, 2H).

MS (ES) ^(m)/z 267 (M+1).

d) 3-(4-Fluoro-benzyl)-2-thioxanthine

The title compound was prepared in accordance with the general method ofExample 18 (d) but using5,6-diamino-1-(4-fluorobenzyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one(0.55 g, 2.1 mmol), yielding the desired product (0.24 g, 41%).

¹H NMR (DMSO-d₆): δ 13.9 (br s, 1H), 12.5 (s, 1H), 8.15 (s, 1H), 7.44(dd, 2H, J 8.6, 8.6 Hz), 7.12 (t, 2H, J 8.9 Hz), 5.68 (s, 2H).

¹³C NMR (DMSO-d₆): δ 173.96, 160.14, 152.48, 149.28, 141.44, 132.19,129.83 (d, J 8.0 Hz), 115.00 (d, J 22 Hz), 110.82, 49.49.

MS (ES) ^(m)/z 277 (M+1).

EXAMPLE 20 3-Phenethyl-2-thioxanthine a)6-Amino-1-phenethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The title compound was prepared according to the general method ofExample 14 (a) apart from a 3.5 h reaction time at reflux followed byreaction at ambient temperature for 16 h. The product was precipitatedby treatment with dilute acetic acid. Phenethylthiourea (1.0 g, 5.6mmol) afforded the product (1.3 g, 95%) as a white solid.

¹H NMR (DMSO-d₆): δ 11.8 (br s, 1H), 7.37 (d, 2H, J 7.1 Hz), 7.31 (t,2H, J 7.4 Hz), 7.22 (t, 1H, J 7.2 Hz), 7.08 (br s, 2H), 4.88 (s, 2H),4.52 (br s, 1H), 3.32 (br s, 1H), 2.92 (t, 2H, J 8.3 Hz).

MS (ES) ^(m)/z 248 (M+1).

b) 6-Amino-5-nitroso-1-phenethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The title compound was prepared according to the general method ofExample 14 (b) except increasing the reaction time to 1.5 h.6-Amino-1-phenethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (1.3 g, 5.3mmol) afforded the desired product (1.3 g, 92%).

¹H NMR (DMSO-d₆): δ 13.5 (br s, 1H), 12.8 (br s, 1H), 9.34 (br s, 1H),7.37-7.28 (m, 4H), 7.25-7.20 (m, 1H), 4.55 (br s, 2H), 2.90 (t, 2H, J8.4 Hz).

c) 5,6-Diamino-1-phenethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one

The title compound was prepared in accordance with the general method ofExample 14 (c) except that the reaction was kept at 75° C. for 15minutes followed by 1 h and 20 minutes at ambient temperature andneutralization of the reaction mixture was made with dilute acetic acid.Using6-amino-5-nitroso-1-phenethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one(1.3 g, 4.8 mmol) the desired product (1.1 g, 88%) was isolated.

¹H NMR (DMSO-d₆): δ 10.1 (br s, 2H), 7.46-7.16 (m, 5H), 6.25 (s, 2H),4.56 (br s, 2H), 2.94 (t, 2H, J 8.3 Hz).

MS (ES) ^(m)/z 263 (M+1).

d) 3-Phenethyl-2-thioxanthine

The title compound was prepared in accordance with the general method ofExample 18 (d) with the exception that for the final neutralization 1Mhydrochloric acid was utilized. Using5,6-diamino-1-phenethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.55 g,2.1 mmol) yielded the desired product (0.39 g, 34%).

¹H NMR (DMSO-d₆): δ 7.53 (s, 1H), 7.32 (d, 4H, J 4.5 Hz), 7.22 (m, 1H),4.63 (m, 2H), 3.01 (m, 2H), 1.88 br s, 2H).

¹³C NMR (DMSO-d₆): δ 170.56, 155.20, 150.51, 146.41, 138.54, 128.58,128.46, 126.34, 117.49, 48.82, 32.59.

MS (ES) ^(m)/z 273 (M+1).

EXAMPLE 21 Enantiomers of 3-(2-Tetrahydrofuryl-methyl)-2-thioxanthine

A solution of racemic 3-(2-tetrahydrofuryl-methyl)-2-thioxanthine (3mg/mL) was separated by chiral HPLC on a Chiralpak AD-RH column (4.6×150mm; 5 μm). The mobile phase was methanol:acetic acid:triethylamine(100:0.1:0.1) and the flow rate 1 mL/min. The injection volume was 20μL.

Enantiomer 1

e.e. 93.6%; MS (ES) ^(m)/z 253 (M+1).

Enantiomer 2

e.e. 97.3%; MS (ES) ^(m)/z 253 (M+1).

EXAMPLE 22 3-n-Butyl-2-thioxanthine

The title compound was prepared using the procedure described forExample 6.

¹H NMR (DMSO-d₆): δ 13.82 (s, 1H), 12.40 (s, 1H), 8.15 (s, 1H), 4.45 (m,2H), 1.73 (m, 2H), 1.34 (sextet, 2H, J=7.5), 0.92 (t, 3H, J=7.5).

¹³C NMR (DMSO-d₆): δ 173.31, 152.62, 149.30, 141.47, 110.84, 47.37,28.61, 19.48, 13.72.

MS (ES) ^(m)/z 225 (M+1).

Screens

Methods for the determination of MPO inhibitory activity are disclosedin co-pending patent application WO 02/090575. The pharmacologicalactivity of compounds according to the invention was tested in thefollowing screen:

Assay buffer: 20 mM sodium/potassium phosphate buffer pH 6.5 containing10 mM taurine and 100 mM NaCl.

Developing reagent: 2 mM 3,3′,5,5′-tetramethylbenzidine (TMB), 200 μMKI, 200 mM acetate buffer pH 5.4 with 20% DMF.

To 10 μl of diluted compounds in assay buffer, 40 μl of human MPO (finalconcentration 2.5 nM) was added for 10 minutes at room temperature. Then50 μl of H₂0₂ (final concentration 100 μM), or assay buffer alone as acontrol, were added for 10 minutes at room temperature. The reaction wasstopped by adding 10 μl 0.2 mg/ml of catalase (final concentration 18μg/ml) for 5 minutes before 100 μl of TMB developing reagent was added(2 mM TMB in 200 mM acetate buffer pH 5.4 containing 20%dimethylformamide (DMF) and 200 μM KI). Plates were mixed and the amountof oxidised 3,3′,5,5′-tetramethylbenzidine formed was then measuredafter about 5 minutes using absorbance spectroscopy at about 650 nM.IC₅₀ values were then determined using standard procedures.

When tested in the above screen, the compounds of Examples 1 to 22 gaveIC₅₀ values of less than 60 μM, indicating that they are expected toshow useful therapeutic activity. Representative results are shown inthe following Table:

Compound Inhibition of MPO (IC₅₀ μM) Example 6 0.87 Example 10 0.53Example 14 0.51 Example 15 0.44 Example 16 2.94 Example 17 7.57 Example18 0.49 Example 20 0.96

1. A compound of the following formula

wherein R² represents (C₁-C₆) alkyl substituted by (C₁-C₆) alkoxy, or apharmaceutically acceptable salt thereof.